DOES TACHYPHYLAXIS OCCUR TO THE NON-PULMONARY EFFECTS OF SALMETEROL

1 The potential for tachyphylaxis to the non-pulmonary effects of salm eterol, a long-acting selective beta(2)-adrenoceptor agonist was inves tigated in 12 healthy male subjects in a double-blind two period cross over study design. 2 Subjects received cumulative doses of up to 400 m u g (50+50+100+100+100 mu g at 45 min intervals) inhaled salmeterol pr ior to a 13 day dosing schedule of twice-daily inhaled salmeterol 100 mu g or placebo. Twelve hours after the last dose of salmeterol or pla cebo, subjects again received cumulative doses of up to 400 mu g inhal ed salmeterol. 3 Pulse rate, blood pressure, 12-lead ECG, physiologica l tremor and peak expiratory flow rate (PEFR) were measured before adm inistration of cumulative doses of salmeterol, at 10, 20, 30 and 40 mi n after each incremental dose of salmeterol and at 4, 6 and 8 h after the first dose. Blood samples were taken for plasma potassium, magnesi um, non-esterified fatty acids (NEFA) and blood glucose concentrations at 20 and 40 min after each dose and at 4, 6 and 8 h after the first dose. 4 Eleven subjects completed the study. One subject withdrew due to beta(2)-adrenoceptor related adverse events. All other adverse even ts reported were mild in nature. 5 Dose-related changes to the effects of salmeterol on pulse rate, QTc interval, tremor, PEFR, blood glucos e and plasma potassium were seen, but there was no dose-related effect of salmeterol on blood pressure, plasma magnesium and NEFA. 6 Tachyph ylaxis occurred to the effects of salmeterol on tremor, QTc and blood glucose. There was no tachyphylaxis to the effects on plasma potassium . Changes in baseline readings after salmeterol made interpretation of the effects seen on pulse rate and PEFR difficult to assess.